Bis esters of iodinated phenyl aliphatic carboxylic acids



Patented Oct. 9, 1945 I oN rE :I TATES ATENT, OFFICE v a 1 2,386,640 v I ms ESTERS F IODINATEDPHENYL a AIJTBATIUOARBOXYLIGAGIDS- I 1Q William Strain, Rochester, N. Y.,

.1 i V Plati, Passaic, N. 'J., and Stafford L.

' c Tenn, assignors of ;one-half to j john, Warren,

f-j-Noned Corporation, and one-half to Eastman Kodak Companmboth of Rochester, N. Y., a corporation'ofNew Jersey r,

No Drawing. Application May 5,1944, a

Serial No. 534,348

50mins. (01. 250-476) invention relates to bis esters ofiodinated phenyl' ahphatic carboxylicacids, useful as contrast media in. radiography, roentgenography. or

skiagraphy, .andto a' process for the preparation of; such esters. Thisjapplioation is .a continuation-impart of our copending application Serial No.1339,9$12, filed June 11,1940 (now United States i Patent 2,348,231, dated May 9, 1944) i'f 'ItiS vknown tha't certain h logen'at'ed vegetable o1ls, su ch as iodinatedj rapeseed, poppyseed or chloriodin'ated "peanut oil, can be employed to produce radiopacity;"'.,Such preparations suffer ,fromithe, defects thatthey cannot besterilized and; are,,poorlyf absorbed byxthe body i tissues.

. Furthermore, whefifthese compounds are introduced into certain cavities of,the-body, such as I the ,subarachnoid; spac 1 oflth'e spinal column or the'braincavity, they are :not eliminated, by. the body and bythincontinuedpresence may cause serious damage to vital parts. I

our parent application 339,912, we have disclosed both mono landbis; estersof iodinated ,phenyl aliphatic 'c'arboxylic; acids. These esters are; all free-flowing liquids; (although 'th -bis esters are more viscous thanthe mono), andare suited particularly-for the"production of radiofound it advantageous to effect the esterification pacity fin those 7. parts of lithe body 7 where there are natural'cavities, or where cavities have been producedby accident orby operation; The in- ,stant application is directed particularly to the glgisester's and their preparation. 5 These'bis esters are especially suited for the production of 'opacity Q};

bronchial passages, sinuses, fistulae'and "emprem xce it i'feiiifesents a 'm he a c edl rmn the group; consisting; of saturated acyclic hydro- I) i;

Lear nj groupshaving n tl sjthani l c rbpn gat nb retha c rbonatomsi w represent a. w ole umber notis eet ,tha

lan gm e r s n s alqira nt ica -sele edfmm the groupv consist n -9i whrem mnd m have-:the'ivalues.

given "above;

' water," to remove In accordance with our invention,..wef prepare the above formulatedibis esters by. esterifying ethylene glycol, trimethylene glycol (LB-propylene glycol), 1,2-propylene glycol or glycerol with an iodinated phenyl; aliphatic carboxylic acid 7 of the following general formula: i.

o H in).

- vwherein and-,3; have thevaliiesfgiven" above.

The est erification is advantageously carried 1 out in the presence of an acid esterificatiori catalyst, e. g. p-toluenesulfonic acid, Ordinarily, we have by mixing the alcohol andacid together in the presence. of the acid esterification catalyst and heating the mixture forseveral hours? The following examples will lserve to illustrate our new bis esters and the manner-of obtaining the same; In 'the' following'examples,the Par-ts given are by weight.

"Examplef,Ethylehe-bis-[b-(p iodophenyloialer- "A mixture or 31 parts of ethylene glycol, 304

parts of 6-(p-iodophenyll-valeric acid andv 10 parts of p-toluenesulfonic acid were heated tov gether at nitrogen was passed through the mixture: The mixture 'was cooled, the chloroform 'C. for 3 hours while a :streamof A mixture of 194 parts of iodophenylundecylic acid, 15.5 parts of ethylene glycol and 2 parts of p-toluenesulfonic acid was heated at'150 C. for three hours while a, gentle stream of nitrogen was bubbled through the mixture. The reaction mix- 1 ture was, then cooled and taken :up in chloroform.

Following drying the chloroform was removed by distillation. The residue was taken up in petroleum ether and. the resuiting solution decolorized with activated char- The solvent was removed from the de- 3 coal. colorized solution under reduced pressure. The product remaining was the his ester. It was obtained as a pale yellow viscousoil; Thebisester was essentially ethylene bis (p-iodophenylundecylate.

Example 3.Trimethylene bis-(iodophnyzumae= cylate) A mixture of 155 parts of p-iodophenylundecylic acid, 15.2 parts of trimethylene glycol and 2 parts of p-toluene-sulfonic acid was heated under an esterifying column for 1 /2 hours in an oil bath maintained at 175 C.,'the Water formed during the e'sterification being taken off as the esterification proceeded. At the end of 1 hours, the reaction mixture was cooled to ordinary room temperature and then taken up in 100 volumes of chloroform. The chloroform solution was washed with 50 volumes of warm water, then with two 50'- volume portions of 2 per cent (by weight) aqueous potassium carbonate solution, and finally with two 50-volume portions of warm water. The washed chloroform solution was then dried over anhydrous sodium sulfate. The dried solution was. decolorized with activated charcoal and the chloroform was removed by heating on a steam bath.

. The product which remained was the bis ester. It

was obtained as a tasteless, odorless viscous oil. This ester was essentially trimethylene bis-(piodophenylundecylate) Example 4.Propylene bis-(idodphenylundecylate) The reaction mixture was cooled and the reaction product takenout in chloroform. The chlo- .through the mixture.

6.(p-i0dophenyl)-va1eric acid and 10 parts of ptoluenesulfonic acid was. heated at 150 C. for 3 hours, while a stream of nitrogen was passed The reaction product was cooled and taken up in chloroform. The chloroform solution was washed with water and then with dilute aqueous sodium carbonate solution and. finally with water.

Th washed chloroform solution was. treated with activated charcoal to decolorize it. The. decolorized chloroform solution wasldistilled on a steam bath to remove the chloroform. The viscous oil remaining was the bis ester.

roform solution wa s'washed with water, then with dilute aqueous sodium carbonate solution and finally with water. Thechloroform solution was dried over anhydrous sodium sulfate and the chloroform removed by distillation on 'a steam bath.

' The residue was taken up in petroleum ether, the

petroleum ether solution decc-lorized with activated charcoal and the petroleum ether: removed under reduced pressure. The product remaining was the his ester. It was obtained as a pale yellow viscous oil. which was odorless and'tasteless. This ester was essentially 1,2-propylene bis (p-iodophenylundecylate) Example 5.--Glyce'ryl tri-[a- (p-z'ddophenyl) 'ualeratel II om-o-o-(omhOr Example 6:'-Glyceryl tri-iodophenylundecylate sodium carbonate solution and finally with water.

The washed chloroform solution was then dried over anhydrous sodium sulfate. The chloroform was then removed from the solution by distillation on a steam bath. The residue was taken up in petroleum ether and the solution decolorized with activated charcoal. The petroleum ether was removed under reduced pressure. An excellent yield bis ester remained as a pale yellow viscous oil. This ester was essentially glyceryl tri-(p-iodophenylundecylate) h In a manner similar to that illustrated in the foregoing examples, bis esters can be prepared from other iodinated aliphatic carboxylic acids. Phenyl aliphatic carboxylic acids are known and reference to their preparation is given by Strain, Plati and Warren in J. Am. Chem. Soc., 65, 1273 (1943). Allvof these phenyl aliphatic carboxylic acids can be iodinated according to the methods given in the aforesaid publication by Strain, Plati and Warren. The following example illustrates the iodination of phenylundecylic acid.

Example 7;--Iodophenyl undecylic acid To a solution of 610 parts of iodine in 4000 parts of glacial acetic acid at C., were added 400 volumes of sulfuric acid, 1572 parts of phenylundecylic' acid (prepared according-to Fourneau and Barangar, Bull. soc.- chim., 49, 1161 (1931)), and 2'78 parts of sodiumv iodate dissolved in 700 volumes of water. The mixture was heated with stirring under reflux until the iodine color disappeared (5 to 15 minutes), and then for an additional 5 minutes. (As the iodine color reappears, it is destroyed by the addition of a small amountvof saturated aqueous sodium iodate solution.) When the reaction was complete, the hot reaction mixture was poured onto 500 parts of cracked ice and any free iodine, iodateion and chlorate ion. were reduced. by the addition of isomers which can be represented by the following formulas: a

and

Accordingly, the iodinated phenylundecylic acid obtained in this example is a mixture of two isomers corresponding to the formulas given immediately above. In both isomers, the iodine goes into the benzene ring principally to the para position oi the aliphatic group. The bis esters prepared from such iodophenylundecylic acid are likewise mixtures of isomers corresponding to the above formulated phenylundecylic acids. In other words, the bis ester of Example 4 is principally a mixture of two esters which can be represented by the following formulas:

CH: O

CH3 CH3 What we claim as our invention and desire to be secured by Letters Patent of the United States is:

1. The bis esters having the following general formula:

ll I QR 0-0-111-0-0-11 wherein R represents a member selected from wherein R and a: have the values given above.

2. The bis esters having the following general formula:

wherein R represents a member selected from the group consisting of saturated acyclic hydrocarbon groups having not less than 4 and not more than 18 carbon atoms, and. R1 represents a divalent radical selected from the group consisting of CH2CH2-, CH2CH2-CH2-,

-CHrCH-- onm I wherein R has the value given above.

3. Trimethylene bis (iodophenylundecylate). 4. 1,2 propylene bis (iodophenylundecylate). 5. Ethylene bis [6-(p-iodophenyl) -va1eratel.

WILLIAM H. STRAIN. JOHN T. PLA'I'I. STAFFORD L. WARRENA 

